Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of “stemness,” such as self-renewal, in cancer. Yet little is known about the function Zeb1 adult stem cells. Here, we used hematopoietic system well-established paradigm cell biology to evaluate Zeb1-mediated regulation We employed conditional genetic approach using Mx1-Cre specifically knock out (KO) cells (HSCs) and their downstream progeny. Acute deletion led rapid-onset thymic atrophy apoptosis-driven loss thymocytes T A profound cell-autonomous self-renewal defect multilineage differentiation block were observed Zeb1-KO HSCs. Loss HSCs activated transcriptional programs deregulated HSC maintenance genes polarity consisting cytoskeleton-, lipid metabolism/lipid membrane–, adhesion–related genes. Notably, epithelial adhesion molecule (EpCAM) expression was prodigiously upregulated HSCs, which correlated with enhanced survival, diminished mitochondrial metabolism, ribosome biogenesis, capacity an transcriptomic signature associated acute myeloid leukemia (AML) signaling. ZEB1 downregulated AML patients, KO malignant counterparts — leukemic (LSCs) accelerated MLL-AF9– Meis1a/Hoxa9-driven progression, implicating tumor suppressor LSCs. Thus, acts regulator hematopoiesis, critically coordinating apoptotic, fates required suppress potential AML.